Search

Background: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar–Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. Methods: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. Results: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. Conclusions: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Macroautophagy/autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that autophagy is impaired during cerebral ischemia, contributing to neuronal dysfunction and neurodegeneration. However, the outcomes after transient modification in autophagy machinery are not fully understood. This study investigated the effects of ischemic stress on autophagy and synaptic structures using a rat model of oxygen-glucose deprivation (OGD) in hippocampal neurons and a mouse model of middle cerebral artery occlusion (MCAO). Upon acute ischemia, an initial autophagy modification occurred in an upregulation manner. Following, the number of lysosomes increased, as well as lysosomal volume, indicating dysfunctional lysosomal storage. These changes were prevented by inhibiting autophagy via 3-methyladenine (3-MA) treatment or ATG7 (autophagy related 7) knockdown, or were mimicked by rapamycin (RAPA), a known activator of autophagy. This suggests that dysfunctional lysosomal storage is associated with the early burst of autophagy. Dysfunctional lysosomal storage contributed to autophagy dysfunction because the basal level of MTOR-dependent lysosomal biogenesis in the reperfusion was not sufficient to clear undegraded cargoes after transient autophagy upregulation. Further investigation revealed that impairment of synaptic ultra-structures, accompanied by dysfunctional lysosomal storage, may result from a failure in dynamic turnover of synaptic proteins. This indicates a vital role of autophagy-lysosomal machinery in the maintenance of synaptic structures. This study supports previous evidence that dysfunctional lysosomal storage may occur following the upregulation of autophagy in neurons. Appropriate autophagosome-lysosomal functioning is vital for maintenance of neuronal synaptic function and impacts more than the few known synaptic proteins. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALR: autophagic lysosome reformation; ATG7: autophagy related 7; CTSB: cathepsin B; CTSD: cathepsin D; DAPI: 4ʹ,6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DMEM: Dulbecco’s modified Eagle’s medium; DMSO: dimethyl sulfoxide; GO: Gene Ontology; HBSS: Hanks’ balanced salt solution; HPCA: hippocalcin; i.c.v: intracerebroventricular; KEGG: kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; LSDs: lysosomal storage disorders; MAP2: microtubule-associated protein 2; MCAO: middle cerebral artery occlusion; mCTSB: mature CTSB; mCTSD: mature CTSD; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; OGD/R: oxygen-glucose deprivation/reoxygenation; PBS: phosphate-buffered saline; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; proCTSD: pro-cathepsin D; RAPA: rapamycin; RNA-seq: RNA sequencing; RPS6KB/p70S6K: ribosomal protein S6 kinase; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SIM: Structured Illumination Microscopy; SNAP25: synaptosomal-associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYT1: synaptotagmin I; TBST: tris-buffered saline Tween-20; TEM: transmission electron microscopy; TFEB: transcription factor EB; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; TUBB3: tubulin, beta 3 class III.

Treatment of central nervous system (CNS) demyelination is greatly hindered by lack of the knowledge regarding to underlying molecular mechanisms as well as therapeutic agents. Here, we report a novel small molecule agent, gastrodin (GAS), which can significantly promote CNS myelination in in vivo mice models. By using high-throughput sequencing analysis, we discover a key long non-coding RNA Gm7237 that can enhance CNS myelination and is up-regulated by GAS. Through using bioinformatic analysis and experimental validations, we further unravel that microRNA-142a (miR-142a) and its target myelin gene regulatory factor (MRF) is under the direct regulation by Gm7237. Finally, we demonstrate that Gm7237/miR-142a/MRF axis is the key pathway involved in CNS myelination mediated by GAS. Overall, our results provide not only a novel agent for therapeutic treatment of CNS demyelination but also a molecular basis responsible for GAS-promoted CNS myelination.

Identifying cerebral vulnerability in late life may help prevent or slow the progression of aging-related chronic diseases. However, non-invasive biomarkers aimed at detecting subclinical cerebral changes in the elderly are lacking. Here, we have examined the potential of plasma total tau (t-tau) for identifying cerebral and cognitive deficits in normal elderly subjects. Patterns of cortical thickness and cortical glucose metabolism were used as outcomes of cerebral vulnerability. We found that increased plasma t-tau levels were associated with widespread reductions of cortical glucose uptake, thinning of the temporal lobe, and memory deficits. Importantly, tau-related reductions of glucose consumption in the orbitofrontal cortex emerged as a determining factor of the relationship between cortical thinning and memory loss. Together, these results support the view that plasma t-tau may serve to identify subclinical cerebral and cognitive deficits in normal aging, allowing detection of individuals at risk for developing aging-related neurodegenerative conditions.

Background: Dysfunction of the corticostriatal network has been implicated in the pathophysiology of schizophrenia, but findings are inconsistent within and across imaging modalities. We used multimodal neuroimaging to analyze functional and structural connectivity in the corticostriatal network in people with schizophrenia and unaffected first-degree relatives. Methods: We collected resting-state functional magnetic resonance imaging and diffusion tensor imaging scans from people with schizophrenia (n = 47), relatives (n = 30) and controls (n = 49). We compared seed-based functional and structural connectivity across groups within striatal subdivisions defined a priori. Results: Compared with controls, people with schizophrenia had altered connectivity between the subdivisions and brain regions in the frontal and temporal cortices and thalamus; relatives showed different connectivity between the subdivisions and the right anterior cingulate cortex (ACC) and the left precuneus. Post-hoc t tests revealed that people with schizophrenia had decreased functional connectivity in the ventral loop (ventral striatum–right ACC) and dorsal loop (executive striatum–right ACC and sensorimotor striatum–right ACC), accompanied by decreased structural connectivity; relatives had reduced functional connectivity in the ventral loop and the dorsal loop (right executive striatum–right ACC) and no significant difference in structural connectivity compared with the other groups. Functional connectivity among people with schizophrenia in the bilateral ventral striatum–right ACC was correlated with positive symptom severity. Limitations: The number of relatives included was moderate. Striatal subdivisions were defined based on a relatively low threshold, and structural connectivity was measured based on fractional anisotropy alone. Conclusion: Our findings provide insight into the role of hypoconnectivity of the ventral corticostriatal system in people with schizophrenia.

Quantitative mechanistic modeling of the biological effects of ionizing radiation has a long rich history. Initially, it was dominated by target theory, which quantifies damage caused by traversal of cellular targets like DNA by ionizing tracks. The discovery that mutagenesis, death and/or altered behavior sometimes occur in cells that were not themselves traversed by any radiation tracks but merely interacted with traversed cells was initially seen as surprising. As more evidence of such ‘non-targeted’ or ‘bystander’ effects accumulated, the importance of their contribution to radiation-induced damage became more recognized. Understanding and modeling these processes is important for quantifying and predicting radiation-induced health risks. Here we review the variety of mechanistic mathematical models of nontargeted effects that emerged over the past 2–3 decades. This review is not intended to be exhaustive, but focuses on the main assumptions and approaches shared or distinct between models, and on identifying areas for future research.

Highlights • Development of a biological neural network model that allows long term simulation of brain activity. • Optimization of the model using multiple techniques that led to a speed-up of X200. • Presentation of alternative simulation frameworks for long term simulations., Simulations of neural networks can be used to study the direct effect of internal or external changes on brain dynamics. However, some changes are not immediate but occur on the timescale of weeks, months, or years. Examples include effects of strokes, surgical tissue removal, or traumatic brain injury but also gradual changes during brain development. Simulating network activity over a long time, even for a small number of nodes, is a computational challenge. Here, we model a coupled network of human brain regions with a modified Wilson-Cowan model representing dynamics for each region and with synaptic plasticity adjusting connection weights within and between regions. Using strategies ranging from different models for plasticity, vectorization and a different differential equation solver setup, we achieved one second runtime for one second biological time.

Although more patients survive sepsis and are increasingly discharged from the hospital, they often experience long-term cognitive and psychological impairment with significant socioeconomic impact. However, the pathophysiological mechanisms have not been fully elucidated. In the present study, we showed that LPS induced long-term neurobehavioral abnormities, as reflected by significantly decreased freezing time to context and sucrose preference. Using a high-throughput quantitative proteomic screen, we showed that phosphorylation of synaptic GTPase-activating protein 1 (pSynGAP1) was identified as the hub of synaptic plasticity and was significantly decreased following LPS exposure. This decreased pSynGAP was associated with significantly lower theta and gamma oscillations in the CA1 of the hippocampus. Notably, restoration of pSynGAP1 by roscovitine was able to reverse most of these abnormities. Taken together, our study suggested that pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might play a critical role in long-term neurobehavioral abnormities of sepsis survivors.

The auditory system is a complex sensory network with an orchestrated multilayer regulatory program governing its development and maintenance. Accumulating evidence has implicated long non-coding RNAs (lncRNAs) as important regulators in numerous systems, as well as in pathological pathways. However, their function in the auditory system has yet to be explored. Using a set of specific criteria, we selected four lncRNAs expressed in the mouse cochlea, which are conserved in the human transcriptome and are relevant for inner ear function. Bioinformatic characterization demonstrated a lack of coding potential and an absence of evolutionary conservation that represent properties commonly shared by their class members. RNAscope analysis of the spatial and temporal expression profiles revealed specific localization to inner ear cells. Sub-cellular localization analysis presented a distinct pattern for each lncRNA and mouse tissue expression evaluation displayed a large variability in terms of level and location. Our findings establish the expression of specific lncRNAs in different cell types of the auditory system and present a potential pathway by which the lncRNA Gas5 acts in the inner ear. Studying lncRNAs and deciphering their functions may deepen our knowledge of inner ear physiology and morphology and may reveal the basis of as yet unresolved genetic hearing loss-related pathologies. Moreover, our experimental design may be employed as a reference for studying other inner ear-related lncRNAs, as well as lncRNAs expressed in other sensory systems.

In recent years, the number of patients with neurodegenerative diseases (i.e., Alzheimer's disease, Parkinson's disease, mild cognitive impairment) and mental disorders (i.e., depression, anxiety and schizophrenia) have increased dramatically. Researchers have found that complex network analysis can reveal the topology of brain functional networks, such as small-world, scale-free, etc. In the study of brain diseases, it has been found that these topologies have undergoed abnormal changes in different degrees. Therefore, the research of brain functional networks can not only provide a new perspective for understanding the pathological mechanism of neurological and psychiatric diseases, but also provide assistance for the early diagnosis. Focusing on the study of human brain functional networks, this paper reviews the research results in recent years. First, this paper introduces the background of the study of brain functional networks under complex network theory and the important role of topological properties in the study of brain diseases. Second, the paper describes how to construct a brain functional network using neural image data. Third, the common methods of functional network analysis, including network structure analysis and disease classification, are introduced. Fourth, the role of brain functional networks in pathological study, analysis and diagnosis of brain functional diseases is studied. Finally, the paper summarizes the existing studies of brain functional networks and points out the problems and future research directions.

New findings • What is the central question of this study? We hypothesized that central inflammatory processes that involve activation of microglia and astrocytes contribute to the development of Gαi2 protein-dependent, salt-sensitive hypertension. • What is the main finding and its importance? The main finding is that PVN-specific inflammatory processes, driven by microglial activation, appear to be linked to the development of Gαi2 protein-dependent, salt-sensitive hypertension in Sprague-Dawley rats. This finding might reveal new mechanistic targets in the treatment of hypertension. Abstract The central mechanisms underlying salt-sensitive hypertension, a significant public health issue, remain to be established. Researchers in our laboratory have reported that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the sympathoinhibitory and normotensive responses to high sodium intake in salt-resistant rats. Given the recent evidence of central inflammation in animal models of hypertension, we hypothesized that PVN inflammation contributes to Gαi2 protein-dependent, salt-sensitive hypertension. Male Sprague-Dawley rats received chronic intracerebroventricular infusions of a targeted Gαi2 or control scrambled oligodeoxynucleotide (ODN) and were maintained for 7 days on a normal-salt (NS; 0.6% NaCl) or high-salt (HS; 4% NaCl) diet; in subgroups on HS, intracerebroventricular minocycline (microglial inhibitor) was co-infused with ODNs. Radiotelemetry was used in subgroups of rats to measure mean arterial pressure (MAP) chronically. In a separate group of rats, plasma noradrenaline, plasma renin activity, urinary angiotensinogen and mRNA levels of the PVN pro-inflammatory cytokines TNFα, IL-1β and IL-6 and the anti-inflammatory cytokine IL-10 were assessed. In additional groups, immunohistochemistry was performed for markers of PVN and subfornical organ microglial activation and cytokine levels and PVN astrocyte activation. High salt intake evoked salt-sensitive hypertension, increased plasma noradrenaline, PVN pro-inflammatory cytokine mRNA upregulation, anti-inflammatory cytokine mRNA downregulation and PVN-specific microglial activation in rats receiving a targeted Gαi2 but not scrambled ODN. Minocycline co-infusion significantly attenuated the increase in MAP and abolished the increase in plasma noradrenaline and inflammation in Gαi2 ODN-infused animals on HS. Our data suggest that central Gαi2 protein prevents microglial-mediated PVN inflammation and the development of salt-sensitive hypertension.

BACKGROUND AND PURPOSE In the sensorimotor (SM) and medial prefrontal (mPF) basal ganglia (BG) circuits, the cortical information is transferred to the substantia nigra pars reticulata (SNr) through the hyperdirect trans-subthalamic pathway and through the direct and indirect trans-striatal pathways. The cannabinoid CB1 receptor, which is highly expressed in both BG circuits, may participate in the regulation of motor and motivational behaviours. Here, we investigated the modulation of cortico-nigral information transmission through the BG circuits by cannabinoids. EXPERIMENTAL APPROACH We used single-unit recordings of SNr neurons along with simultaneous electrical stimulation of motor or mPF cortex in anaesthetized rats. KEY RESULTS Cortical stimulation elicited a triphasic response in the SNr neurons from both SM and mPF-BG circuits, which consisted of an early excitation (hyperdirect transmission pathway), an inhibition (direct transmission pathway), and a late excitation (indirect transmission pathway). In the SM circuit, after Δ9 -tetrahydrocannabinol or WIN 55,212-2 administration, the inhibition and the late excitation were decreased or completely lost, whereas the early excitation response remained unaltered. However, cannabinoid administration dramatically decreased all the responses in the mPF circuit. The CB1 receptor antagonist AM251 (2 mg·kg-1 , i.v.) did not modify the triphasic response, but blocked the effects induced by cannabinoid agonists. CONCLUSIONS AND IMPLICATIONS CB1 receptor activation modulates the SM information transmission through the trans-striatal pathways and profoundly decreases the cortico-BG transmission through the mPF circuit. These results may be relevant for elucidating the involvement of the cannabinoid system in motor performance and in decision making or goal-directed behaviour.

Background and purpose Temporomandibular disorders (TMD) and migraine can be co-morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine-like symptoms. However, the underlying mechanisms involved are unknown. Our objective was to investigate these neural mechanisms and the role of CGRP as a key modulator in this co-morbidity. Experimental approach We combined experimental approaches using CGRP, which triggers a migraine-like response in patients, with that of masseteric muscle injection of complete Freund's adjuvant (CFA), to model myofascial TMD-like inflammation. Using validated electrophysiological methods to assess each of the above approaches independently or in combination, we examined their effects on the response properties of migraine-like dural-trigeminocervical neurons. Key results Independently, in ~2/3 of animals (rats) each approach caused delayed migraine-like activation and sensitisation of dural-trigeminocervical neurons. The response to masseteric-CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine-like neuronal response in all animals tested, with somatosensory-evoked cranial hypersensitivity significantly exacerbated. Conclusion and implications The data demonstrate a neuronal phenotype that translates to the exacerbated clinical co-morbid phenotype, supporting this combination approach as a relevant model to study the mechanisms involved. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating the involvement of CGRP. The results provide support for targeting the CGRP pathway as a novel monotherapy approach for treating this co-morbid condition. This has key implications into our understanding of this co-morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches.

Cerebellar ataxia is the predominant motor feature of multiple system atrophy cerebellar subtype (MSA-C). Although repetitive transcranial magnetic stimulation (TMS) of the cerebellum is growingly applied in MSA, the mechanism is unknown. We examined dynamic connectivity changes of 20 patients with MSA and 25 healthy controls using TMS combined with electroencephalography. Observations that significantly decreased dynamic cerebello-frontal connectivity in patients have inspired attempts to modulate cerebellar connectivity in order to benefit MSA. We further explore the therapeutic potential of a 10-day treatment of cerebellar intermittent theta burst stimulation (iTBS) in MSA by a randomized, double-blind, sham-controlled trial. The functional reorganization of cerebellar networks was investigated after the end of treatment in active and sham groups. The severity of the symptoms was evaluated using the Scale for Assessment and Rating of Ataxia scores. Patients treated with active stimulation showed an improvement of cerebello-frontal connectivity and balance functions, as revealed by a significant decrease in the ataxia scores (P < 0.01). Importantly, the neural activity of frontal connectivity from 80 to 100 ms after a single TMS was significantly related to the severity of the disease. Our study provides new proof that cerebellar iTBS improves motor imbalance in MSA by acting on cerebello-cortical plasticity.

The Y-group plays an important role in the generation of upward smooth pursuit eye movements and contributes to the adaptive properties of the vertical vestibulo-ocular reflex. Malfunction of this circuitry may cause eye movement disorders, such as downbeat nystagmus. To characterize the neuron populations in the Y-group, we performed immunostainings for cellular proteins related to firing characteristics and transmitters (calretinin, GABA-related proteins and ion channels) in brainstem sections of macaque monkeys that had received tracer injections into the oculomotor nucleus. Two histochemically different populations of premotor neurons were identified: The calretinin-positive population represents the excitatory projection to contralateral upgaze motoneurons, whereas the GABAergic population represents the inhibitory projection to ipsilateral downgaze motoneurons. Both populations receive a strong supply by GABAergic nerve endings most likely originating from floccular Purkinje cells. All premotor neurons express nonphosphorylated neurofilaments and are ensheathed by strong perineuronal nets. In addition, they contain the voltage-gated potassium channels Kv1.1 and Kv3.1b which suggests biophysical similarities to high-activity premotor neurons of vestibular and oculomotor systems. The premotor neurons of Y-group form a homogenous population with histochemical characteristics compatible with fast-firing projection neurons that can also undergo plasticity and contribute to motor learning as found for the adaptation of the vestibulo-ocular reflex in response to visual-vestibular mismatch stimulation. The histochemical characterization of premotor neurons in the Y-group allows the identification of the homologue cell groups in human, including their transmitter inputs and will serve as basis for correlated anatomical-neuropathological studies of clinical cases with downbeat nystagmus.

The ability to generate in vitro cultures of neuronal cells has been instrumental in advancing our understanding of the nervous system. Rodent models have been the principal source of brain cells used in primary cultures for over a century, providing insights that are widely applicable to human diseases. However, therapeutic agents that showed benefit in rodent models, particularly those pertaining to aging and age-associated dementias, have frequently failed in clinical trials. This discrepancy established a potential “translational gap” between human and rodent studies that may at least partially be explained by the phylogenetic distance between rodent and primate species. Several non-human primate (NHP) species, including the common marmoset (Callithrix jacchus), have been used extensively in neuroscience research, but in contrast to rodent models, practical approaches to the generation of primary cell culture systems amenable to molecular studies that can inform in vivo studies are lacking. Marmosets are a powerful model in biomedical research and particularly in studies of aging and age-associated diseases because they exhibit an aging phenotype similar to humans. Here, we report a practical method to culture primary marmoset neurons and astrocytes from brains of medically euthanized postnatal day 0 (P0) marmoset newborns that yield highly pure primary neuron and astrocyte cultures. Primary marmoset neuron and astrocyte cultures can be generated reliably to provide a powerful NHP in vitro model in neuroscience research that may enable mechanistic studies of nervous system aging and of age-related neurodegenerative disorders. Because neuron and astrocyte cultures can be used in combination with in vivo approaches in marmosets, primary marmoset neuron and astrocyte cultures may help bridge the current translational gap between basic and clinical studies in nervous system aging and age-associated neurological diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00284-z) contains supplementary material, which is available to authorized users.

Traumatic brain injury (TBI) is regarded as a high-risk factor for Alzheimer's disease (AD). Asparaginyl endopeptidase (AEP), a lysosomal cysteine protease involved in AD pathogenesis, is normally activated under acidic conditions and also in TBI. However, both the molecular mechanism underlying AEP activation-mediated TBI-related AD pathologies, and the role of AEP as an AD therapeutic target, still remain unclear. Here, we report that TBI induces hippocampus dependent cognitive deficit and synaptic dysfunction, accompanied with AEP activation, I2PP2A (inhibitor 2 of PP2A, also called SET) mis-translocation from neuronal nucleus to cytoplasm, an obvious increase in AEP interaction with SET, and tau hyperphosphorylation in hippocampus of rats. Oxygen-glucose deprivation (OGD), mimicking an acidic condition, also leads to AEP activation, SET mis-translocation, PP2A inhibition, tau hyperphosphorylation, and a decrease in synaptic proteins, all of which are abrogated by AEP inhibitor AENK in primary neurons. Interestingly, AENK restores SET back to the nucleus, mitigates tau pathologies, rescuing TBI-induced cognitive deficit in rats. These findings highlight a novel etiopathogenic mechanism of TBI-related AD, which is initiated by AEP activation, accumulating SET in cytoplasm, and favoring tau pathology and cognitive impairments. Lowering AEP activity by AEP inhibitor would be beneficial to AD patients with TBI.

The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8+ cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3+, CD4+ and CD8+) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3+ and CD8+ cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.

Key points Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase.Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non‐image forming visual structures.We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN.Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)‐activating peptide/PAC1 receptor systems (used by melanopsin‐expressing retinal ganglion cells), which directly regulates responses to the retinal input.These results help us better understand circadian orexinergic control over the non‐image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night. Abstract The orexinergic system of the lateral hypothalamus is tightly interlinked with the master circadian clock and displays daily variation in activity to provide arousal‐related excitation for the plethora of brain structures in a circadian manner. Here, using a combination of electrophysiological, optogenetic, histological, molecular and neuronal tracing methods, we explore a particular link between orexinergic and visual systems in rat. The results of the present study demonstrate that orexinergic fibre density at the area of subcortical visual system exerts a clear day to night variability, reaching a maximum at behaviourally active night. We also show pronounced electrophysiological activations of neurons in the lateral geniculate nucleus by orexin A through 24 h, via identified distinct orexin receptors, with the ventrolateral geniculate displaying a daily cycle of responsiveness. In addition, for the first time, we provide a direct evidence for orexins to act on retinorecipient neurons with a high convergence of orexinergic and putatively retinal pituitary adenylate cyclase (PAC)‐activating peptide/PAC1 receptor systems. Altogether, the present study ties orexins to non‐image forming visual structures with implications for circadian orexinergic modulation of neurons, which process information on ambient light levels., Key points Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase.Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non‐image forming visual structures.We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN.Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)‐activating peptide/PAC1 receptor systems (used by melanopsin‐expressing retinal ganglion cells), which directly regulates responses to the retinal input.These results help us better understand circadian orexinergic control over the non‐image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night.

Background and purpose Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored. Experimental approach The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. Key results Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant. Conclusion and implications Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.

Obesity is a major health challenge facing many people throughout the world. Increased consumption of palatable, high-caloric foods is one of the major drivers of obesity. Both orexigenic and anorexic states have been thoroughly reviewed elsewhere; here, we focus on the cognitive control of feeding in the context of obesity, and how the orbitofrontal cortex (OFC) is implicated, based on data from preclinical and clinical research. The OFC is important in decision-making and has been heavily researched in neuropsychiatric illnesses such as addiction and obsessive–compulsive disorder. However, activity in the OFC has only recently been described in research into food intake, obesity and eating disorders. The OFC integrates sensory modalities such as taste, smell and vision, and it has dense reciprocal projections into thalamic, midbrain and striatal regions to fine-tune decision-making. Thus, the OFC may be anatomically and functionally situated to play a critical role in the etiology and maintenance of excess feeding behaviour. We propose that the OFC serves as an integrative hub for orchestrating motivated feeding behaviour and suggest how its neurobiology and functional output might be altered in the obese state.

Many relevant aspects of mammal’s cardiac physiology have been mainly investigated in insect models such as Drosophila melanogaster and Periplaneta americana. Cardiac function has been poorly studied in the cockroach Gromphadorhina portentosa, which has some advantages for experimental purposes such as an easier culture, bigger organs and a robust physiology. On the other hand, the study of cardiac physiology in insects has been largely improved since the arrival of digital imaging technologies for recording purposes. In the present work, we introduce a methodology of video recording coupled to an isotonic transducer for a three-dimensional analysis of the heart and intracardiac valves of G. portentosa. We used this methodology for assessing the physiological responses of the cockroach heart upon the application of different cholinergic neurotransmitters (acetylcholine, nicotine and muscarine). We recorded in detail the relationship between intracardiac valves movement, hemolymph flow, diastole and systole. Acetylcholine and nicotine induced a biphasic effect on the cardiac frequency. Acetylcholine increased the diastolic opening. Nicotine at high concentration caused paralysis. Muscarine induced no major effects. These findings suggest a combined action of cholinergic agonists for a finely tuned the cardiac frequency, intracardiac valves function and cardiac cycle. Electronic supplementary material The online version of this article (10.1007/s00359-020-01443-5) contains supplementary material, which is available to authorized users.

Caudate dopaminergic dysfunction is implied in the pathophysiology of patients with Parkinson's disease (PD). Still, connectivity specificities of the caudate nucleus (CN) subdivisions and the effect of dopamine are poorly understood. We collected MRI and neuropsychological data from 34 PD patients and 26 age- and sex-matched healthy elderly individuals (HEs) in this study. Resting-state functional connectivity analysis revealed that compared to the other CN subdivisions, the CN head was more strongly connected to the default mode network (DMN), the CN body to the frontoparietal network (FPN), and the CN tail to the visual network in HEs. PD patients off medication showed reduced connectivity within all these subdivision networks. In PD patients on medication, functional connectivity in the CN head network was significantly improved in the medial prefrontal cortex and in the body network it was improved in the dorsolateral prefrontal cortex. These improvements contributed to ameliorated motivation and cognitive function in PD patients. Our results highlighted the specific alterations and dopamine modulation in these CN subdivision networks in PD, which may provide insight into the pathophysiology and therapeutics of this disease.

Understanding the microstructural changes related to physiological aging of the cerebral cortex is pivotal to differentiate healthy aging from neurodegenerative processes. The aim of this study was to investigate the age-related global changes of cortical microstructure and regional patterns using multiparametric quantitative MRI (qMRI) in healthy subjects with a wide age range. 40 healthy participants (age range: 2nd to 8th decade) underwent high-resolution qMRI including T1, PD as well as T2, T2* and T2′ mapping at 3 Tesla. Cortical reconstruction was performed with the FreeSurfer toolbox, followed by tests for correlations between qMRI parameters and age. Cortical T1 values were negatively correlated with age (p=0.007) and there was a widespread age-related decrease of cortical T1 involving the frontal and the parietotemporal cortex, while T2 was correlated positively with age, both in frontoparietal areas and globally (p=0.004). Cortical T2′ values showed the most widespread associations across the cortex and strongest correlation with age (r= -0.724, p=0.0001). PD and T2* did not correlate with age. Multiparametric qMRI allows to characterize cortical aging, unveiling parameter-specific patterns. Quantitative T2′ mapping seems to be a promising imaging biomarker of cortical age-related changes, suggesting that global cortical iron deposition is a prominent process in healthy aging.

Previous work has shown that α2/α3GABAAR-selective modulators normalize neuropathic and inflammatory hyperalgesia. Here, we show that they also inhibit the tonic aversive pain component., Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn α2/α3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the α2/α3GABAAR subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli but also was highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that α2/α3GABAA receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.

Background: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. Hypotheses: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. Methods: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. Results: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. Discussion: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

Aims: 22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly ‘shifting’ the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge. Methods: Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined. Results: No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC ( η2 = 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations ( η2 = 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients. Discussion: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Patients with bipolar disorder and schizophrenia often suffer from severe cognitive impairment even during times of remission. This study investigated the pathomechanisms underlying their deficits in cognitive control. A combined oddball–incongruence fMRI task was applied to examine similarities and differences of neural activation patterns between patients and healthy controls. Bipolar and schizophrenia patients demonstrated hyperactivations in the intraparietal cortex during the oddball condition. Furthermore, bipolar patients revealed diagnosis-specific hyperactivation in the left middle frontal gyrus, precentral gyrus, anteroventral prefrontal cortex and orbitofrontal cortex regions compared to schizophrenia patients and healthy individuals. In comparison to healthy controls the patients showed hypoactivations in the inferior frontal junction and ventral pathway during the cognitively more demanding incongruence. Taken together, bipolar patients seem to recruit frontal and parietal areas during the oddball condition to compensate for potential deficits in their attentional network. During more challenging tasks, i.e., the incongruence condition, their compensatory mechanisms seem to collapse leading to hypoactivations in the same frontal areas as well as the ventral pathway.

Anterolateral system neurons in lamina I of the spinal cord rely on DCC for the formation of topographically appropriate nociceptive inputs to the brain., Anterolateral system (AS) neurons relay nociceptive information from the spinal cord to the brain, protecting the body from harm by evoking a variety of behaviours and autonomic responses. The developmental programs that guide the connectivity of AS neurons remain poorly understood. Spinofugal axons cross the spinal midline in response to Netrin-1 signalling through its receptor deleted in colorectal carcinoma (DCC); however, the relevance of this canonical pathway to AS neuron development has only been demonstrated recently. Here, we disrupted Netrin-1:DCC signalling developmentally in AS neurons and assessed the consequences on the path finding of the different classes of spinofugal neurons. Many lamina I AS neurons normally innervate the lateral parabrachial nucleus and periaqueductal gray on the contralateral side. The loss of DCC in the developing spinal cord resulted in increased frequency of ipsilateral projection of spinoparabrachial and spinoperiaqueductal gray neurons. Given that contralateral spinofugal projections are largely associated with somatotopic representation of the body, changes in the laterality of AS spinofugal projections may contribute to reduced precision in pain localization observed in mice and humans carrying Dcc mutations.

Thoracic ganglia of many hearing insects house the first level of auditory processing. In bush-crickets, the largest population of local auditory neurons in the prothoracic processing centre are dorsal unpaired median (DUM) neurons. It has been suggested that DUM neurons are inhibitory using γ-aminobutyric acid (GABA) as transmitter. Immunohistochemistry reveals a population of about 35–50 GABA-positive somata in the posterior medial cluster of the prothoracic ganglion. Only very few small somata in this cluster remain unstained. At least 10 neurites from 10 neurons can be identified. Intracellularly stained auditory DUM neurons have their soma in the cluster of median GABA positive cells and most of them exhibit GABA-immunoreactivity. Responses of certain DUM neurons show obvious signs of inhibition. Application of picrotoxin (PTX), a chloride-channel blocker in insects, changes the responses of many DUM neurons. They become broader in frequency tuning and broader or narrower in temporal pattern tuning. Furthermore, inhibitory postsynaptic potentials (IPSPs) may be replaced by excitatory postsynaptic potentials. Loss of an IPSP in the rising graded potential after PTX-application leads to a significant reduction of first-spike latency. Therefore, auditory DUM neurons receive effective inhibition and are the best candidates for inhibition in DUM neurons and other auditory interneurons. Electronic supplementary material The online version of this article (10.1007/s00359-020-01438-2) contains supplementary material, which is available to authorized users.

Brain complexity, which reflects the ability of the brain to adapt to a changing environment, has been found to be significantly changed with age. However, there is less evidence on the alterations of brain complexity in neurodegenerative disorders such as Alzheimer’s disease (AD). Here we investigated the altered complexity of resting-state blood oxygen level-dependent signals in AD-related neurodegeneration using multiscale entropy (MSE) analysis. All participants were recruited from the Alzheimer’s Disease Neuroimaging Initiative, including healthy controls (HC, n=62), amnestic mild cognitive impairment (aMCI, n =81) patients, and Alzheimer’s disease (AD, n=25) patients. Our results showed time scale-dependent MSE differences across the three groups. In scale=1, significantly changed MSE patterns (HC>aMCI>AD) were found in four brain regions, including the hippocampus, middle frontal gyrus, intraparietal lobe, and superior frontal gyrus. In scale=4, reversed MSE patterns (HC

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)—increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal–striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal ‘brake’. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

During human motor control, the three pathways of motor control coordinate to complete human response and inhibition control, so whether different types of motor skills training will affect the three pathways of motor control is the main question in this study. Magnetic resonance imaging was combined with behavioural evaluation to analyse the effects of different special training sessions on the motor control network of the frontal lobe and basal ganglia and to explore the role of the central nervous system in the regulation of motor behaviour. A Stop-signal paradigm was used to measure reaction and inhibition capacity, functional magnetic resonance imaging was used for whole brain scanning, and resting state data were collected. Compared to the control group, the competitive aerobics athletes had better reflexes while the soccer players had both better reflexes and inhibitory control. Furthermore, we found that training in the two sets of skills resulted in significant differences in different resting state brain function parameters compared with the control group. Additionally, there were significant differences among the three groups in the direct and indirect pathways of motor control in terms of functional connectivity. Open skill training may improve reaction ability while closed skill training improve both reaction and inhibition ability. These results suggest that the strength of the functional connectivity between the right inferior frontal gyrus and the left putamen may be a key to improving the inhibitory, and the left supplementary motor area- bilateral thalamic loop may play an inhibitory role in motor control.

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spatiotemporal dynamics and stability of single and paired pulse TMS-EEG responses, and assess long intracortical inhibition (LICI) at the cortical level. Twenty-five healthy subjects were studied twice, approximately one week apart. Manual coil positioning was applied in sixteen subjects and robot-guided positioning in nine. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at each of the five interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. To assess stability and LICI, the intraclass correlation coefficient and cluster-based permutation analysis were used. We found great resemblance in the topographical distribution of the characteristic TMS-EEG components for single and paired pulse TMS. Stimulation of the dominant and non-dominant hemisphere resulted in a mirrored spatiotemporal dynamics. No significant effect on the TMS-EEG responses was found for either stimulated hemisphere, time or coil positioning method, indicating the stability of both single and paired pulse TMS-EEG responses. For all ISIs, LICI was characterized by significant suppression of the late N100 and P180 components in the central areas, without affecting the early P30, N45 and P60 components. These observations in healthy subjects can serve as reference values for future neuropsychiatric and pharmacological studies. Electronic supplementary material The online version of this article (10.1007/s10548-020-00773-6) contains supplementary material, which is available to authorized users.

This study reveals interfering Notch signaling pathway of anterior cingulate cortex in early phase prevents neuropathic pain progress by inhibiting the potentiation of synaptic transmission., Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain. We adopted Western blotting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings, and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague-Dawley rats. Levels of the Notch intracellular domain were increased in ACC on day 7 after chronic constriction injury surgery or spared nerve injury. Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased, whereas the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA-Notch reduced Notch intracellular domain expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perceptions were also alleviated in rats subjected to chronic constriction injury or spared nerve injury. This process was mainly mediated by the downstream effector Hes1, but not Hes5. Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.

Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuronal disease, characterized by motoneuronal loss and progressive paralysis. Despite research efforts, ALS remains a fatal disease, with a survival of 2-5 years after disease onset. Numerous gene mutations have been correlated with both sporadic (sALS) and familiar forms of the disease, but the pathophysiological mechanisms of ALS onset and progression are still largely uncertain. However, a common profile is emerging in ALS pathological features, including misfolded protein accumulation and a cross-talk between neuroinflammatory and degenerative processes. In particular, astrocytes and microglial cells have been proposed as detrimental influencers of perineuronal microenvironment, and this role may be exerted via gap junctions (GJs)- and hemichannels (HCs)-mediated communications. Herein we investigated the role of the main astroglial GJs-forming connexin, Cx43, in human ALS and the effects of focal spinal cord motoneuronal depletion onto the resident glial cells and Cx43 levels. Our data support the hypothesis that motoneuronal depletion may affect glial activity, which in turn results in reactive Cx43 expression, further promoting neuronal suffering and degeneration.

BACKGROUND AND PURPOSE: Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalisation. Here we assessed the utility of targeting the HCN4 channel as an anti-seizure strategy using pharmacological and genetic approaches. EXPERIMENTAL APPROACH: The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using a HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. KEY RESULTS: EC18 (10mg kg-1 ) and brain-specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant-mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant-mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV-HCN4 shRNA infected mouse cortical cultures. CONCLUSIONS AND IMPLICATIONS: These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti-seizure drugs that is likely to have a low side-effect liability in the central nervous system.

The present study was designed to follow neuroinflammation after ischemic brain injury in the long-term survival rat model. Immunohistochemistry was performed 2 years after 10 min global brain ischemia due to cardiac arrest. For the visualization of the cellular inflammatory reaction microglial marker Iba1 and astrocyte marker GFAP were used. In post-ischemic animals our study revealed significant activation of astrocytes in all tested brain regions (hippocampal CA1 and CA3 areas and dentate gyrus, motor and somatosensory cortex, striatum and thalamus), while microglial activation was only found in CA1 and CA3 areas, and the motor cortex. In the specifically sensitive brain areas microglia and astrocytes showed simultaneously significant activation, while in the resistant brain areas only astrocytes were activated. Thus, there was clear evidence of less intensive neuroinflammation in brain areas resistant to ischemia. Such neuroinflammatory processes are backed by microglia and astrocytes activity even up to 2 years after ischemia-reperfusion brain injury. Our study thus revealed a chronic effect of global cerebral ischemia on the neuroinflammatory reaction in the rat brain even 2 years after the insult.

Aging is a natural human process. It is uniquely individual, taking into account experiences, lifestyle habits and environmental factors. However, many disorders and syndromes, such as osteoporosis, neurodegenerative disorders, cognitive decline etc., often come with aging. The present study was designed to investigate the possible anti-aging effect of N6-(4-hydroxybenzyl)adenine riboside (T1-11), an adenosine analog isolated from Gastrodia elata, in a mouse model of aging created by D-galactose (D-gal) and the underlying mechanism, as well as explore the role of adenosine signaling in aging. T1-11 activated A2AR and suppressed D-gal- and BeSO4-induced cellular senescence in vitro. In vivo results in mice revealed that T1-11 abated D-gal-induced reactive oxygen species generation and ameliorated cognitive decline by inducing neurogenesis and lowering D-gal-caused neuron death. T1-11 could be a potent agent for postponing senility and preventing aging-related neuroinflammation and neurodegeneration.

Introduction In this study, the role of A1 adenosine receptors in improving the effect of Low-Frequency Electrical Stimulation (LFS) on seizure-induced hyperexcitability of hippocampal CA1 pyramidal neurons was investigated. Methods A semi-rapid hippocampal kindling model was used to induce seizures in male Wistar rats. Examination of the electrophysiological properties of CA1 pyramidal neurons of the hippocampus using whole-cell patch-clamp recording 48 h after the last kindling stimulation revealed that the application of LFS as two packages of stimulations at a time interval of 6 h for two consecutive days could significantly restore the excitability CA1 pyramidal neurons evidenced by a decreased in the of the number of evoked action potentials and enhancement of amplitude, maximum rise slope and decay slope of the first evoked action potential, rheobase, utilization time, adaptation index, first-spike latency, and post-AHP amplitude. Selective locked of A1 receptors by the administration of 8-Cyclopentyl-1,3-dimethylxanthine (1 μM, 1 μl, i.c.v.) before applying each LFS package, significantly reduced LFS effectiveness in recovering these parameters. Results On the other hand, selective activation of A1 receptors by an injection of N6-cyclohexyladenosine (10 μM, 1 μl, i.c.v.), instead of LFS application, could imitate LFS function in improving these parameters. Conclusion It is suggested that LFS exerts its efficacy on reducing the neuronal excitability, partially by activating the adenosine system and activating its A1 receptors.

Objective Many population studies have shown that maternal prenatal nutrition deficiency may increase the risk of neurodevelopmental disorders in their offspring, but its potential transcriptomic effects on brain development are not clear. We aimed to investigate the transcriptional regulatory interactions between genes in particular pathways responding to the prenatal nutritional deficiency and to explore their effects on neurodevelopment and related disorders. Results We identified three modules in rat hippocampus responding to maternal prenatal nutritional deficiency and found 15 key genes (Hmgn1, Ssbp1, LOC684988, Rpl23, Gga1, Rhobtb2, Dhcr24, Atg9a, Dlgap3, Grm5, Scn2b, Furin, Sh3kbp1, Ubqln1, and Unc13a) related to the rat hippocampus developmental dysregulation, of which Hmgn1, Rhobtb2 and Unc13a related to autism, and Dlgap3, Grm5, Furin and Ubqln1 are related to Alzheimer's disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for Atg9a. Additionally, through modeling miRNA-mRNA-transcription factor interactions for the hub genes, we confirmed a transcription factor, Cebpa, is essential to regulate the expression of Rhobtb2. We did not find singificent singals in the prefrontal cortex responding to maternal prenatal nutritional deficiency. Conclusion These findings demonstrated that these genes with the three modules in rat hippocampus involved in synaptic development, neuronal projection, cognitive function, and learning function are significantly enriched hippocampal CA1 pyramidal neurons and suggest that three genetic regulatory subnetworks and thirteen key regulating genes in rat hippocampus perturbed by a prenatal nutrition deficiency. These genes and related subnetworks may be prenatally involved in the etiologies of major brain disorders, including Alzheimer's disease, autism, and schizophrenia. Methods We compared the transcriptomic differences in the hippocampus and prefrontal cortex between 10 rats with prenatal nutritional deficiency and 10 rats with prenatal normal chow feeding by differential analysis and co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and hub genes responding to prenatal nutritional deficiency. Meanwhile, the module preservation test was conducted between the hippocampus and prefrontal cortex. Expression levels of the hub genes were further validated with a quantitative real-time polymerase chain reaction based on additional 40 pairs of rats.

Supplemental Digital Content is Available in the Text. DNA methylation undergoes rapid and large changes in mouse prefrontal cortex at multiple time points postinjury, implicating hundreds of genes in a time-dependent manner., Chronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive, and emotional information and in conditioned pain modulation. We previously reported widespread epigenetic reprogramming in the PFC many months after nerve injury in rodents. Epigenetic modifications, including DNA methylation, can drive changes in gene expression without modifying DNA sequences. To date, little is known about epigenetic dysregulation at the onset of acute pain or how it progresses as pain transitions from acute to chronic. We hypothesize that acute pain after injury results in rapid and persistent epigenetic remodelling in the PFC that evolves as pain becomes chronic. We further propose that understanding epigenetic remodelling will provide insights into the mechanisms driving pain-related changes in the brain. Epigenome-wide analysis was performed in the mouse PFC 1 day, 2 weeks, 6 months, and 1 year after peripheral injury using the spared nerve injury in mice. Spared nerve injury resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed between spared nerve injury and sham-operated control mice at all time points. Hundreds of differentially methylated genes were identified, including many with known function in pain. Pathway analysis revealed enrichment in genes related to stimulus response at early time points, immune function at later time points, and actin and cytoskeletal regulation throughout the time course. These results emphasize the importance of considering pain chronicity in both pain research and in treatment optimization.

Purpose Neuropathic pain is a complex and distressing chronic illness in modern medicine. Since 1990s, motor cortex stimulation (MCS) has emerged as a potential treatment for chronic neuropathic pain; however, the precise mechanisms underlying analgesia induced by MCS are not completely understood. The purpose of the present study was to investigate the blood oxygen-level dependent (BOLD) response in the brain during MCS. Methods We inserted a bipolar tungsten electrode into the primary motor cortex (M1) of adult male Wistar rats. Functional magnetic resonance imaging (fMRI) scans were implemented simultaneously with the electrical stimulation of M1 and the BOLD signals taken from the fMRI were used as an index to reflect the response against MCS. Results Our results demonstrated that the bilateral M1, ipsilateral caudate-putamen, and ipsilateral primary somatosensory cortex to the stimulation spot were activated after the onset of MCS. The BOLD signal time courses were analysed in these regions and similar temporal characteristics were found. Conclusion By conducting direct cortical stimulation of the rodent brain to investigate its instant effect using fMRI, we identified encephalic regions directly involved in the instant motor cortical stimulation effects in healthy rat models. This result may be essential in establishing a foundation for further research on the underlying neuropathways associated with the MCS effects.

While amyloid-targeting therapies continue to predominate in the Alzheimer’s disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activity-dependent gene zif-268 mRNA expression. Tremor in rats was induced by harmaline administered at a dose of 15 mg/kg ip. Pramipexole was administered at a low dose of 0.1 mg/kg sc. Tremor was measured by Force Plate Actimeters where four force transducers located below the corners of the plate tracked the animal’s position on a Cartesian plane. The zif-268 mRNA expression was analyzed by in situ hybridization in brain slices. Harmaline induced tremor and increased zif-268 mRNA levels in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei and motor cortex. Pramipexole reversed both the harmaline-induced tremor and the increase in zif-268 mRNA expression in the inferior olive, cerebellar cortex and motor cortex. Moreover, the tremor intensity correlated positively with zif-268 mRNA expression in the above structures. The present results seem to suggest that the tremorolytic effect of pramipexole is related to the modulation of the harmaline-increased neuronal activity in the tremor network which includes the inferior olive, cerebellar cortex and motor cortex. Potential mechanisms underlying the above pramipexole action are discussed.

Using a cross-sectional design, we aimed to identify the effect of aging on sensorimotor function and cortical motor representations of two intrinsic hand muscles, as well as the course and timing of those changes. Furthermore, the link between cortical motor representations, sensorimotor function, and intracortical inhibition and facilitation was investigated. Seventy-seven participants over the full adult lifespan were enrolled. For the first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscle, cortical motor representations, GABAA-mediated short-interval intracortical inhibition (SICI), and glutamate-mediated intracortical facilitation (ICF) were assessed using transcranial magnetic stimulation over the dominant primary motor cortex. Additionally, participants' dexterity and force were measured. Linear, polynomial, and piecewise linear regression analyses were conducted to identify the course and timing of age-related differences. Our results demonstrated variation in sensorimotor function over the lifespan, with a marked decline starting around the mid-thirties. Furthermore, an age-related reduction in cortical motor representation volume and maximal MEP of the FDI, but not for ADM, was observed, occurring mainly until the mid-forties. Area of the cortical motor representation did not change with advancing age. Furthermore, cortical motor representations, sensorimotor function, and measures of intracortical inhibition and facilitation were not interrelated. This work was supported by the Research Fund KU Leuven (C16/15/070), the Research Foundation Flanders grant (G089818N), the Excellence of Science grant (EOS 30446199, MEMODYN) and the Hercules fund AUHL/11/01 (R-3987) and I005018N. The authors declare no competing financial interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Cuypers, K (reprint author), Katholieke Univ Leuven, Dept Movement Sci, Grp Biomed Sci, Movement Control & Neuroplastic Res Grp, Leuven, Belgium; Hasselt Univ, REVAL Res Inst, Agoralaan, Diepenbeek, Belgium. koen.cuypers@kuleuven.be